The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis

OncoTargets and Therapy, Jun 2018

The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis Ke-Li Liao,1 Song Huang,1 Yu-Peng Wu2 1Department of Neurosurgery, Zigong First People’s Hospital, Zigong, Sichuan, People’s Republic of China; 2Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China Background: A combination of temozolomide (TMZ) and radiotherapy and subsequent adjuvant chemotherapy is the gold standard of treatment for glioblastoma (GB). Bevacizumab (BEV), a humanized monoclonal antibody that blocks the effects of vascular endothelial growth factor A, has produced impressive response rates for recurrent GB and has been approved as second-line therapy. The efficacy and safety of BEV in newly diagnosed GB are not known. Aim: This systematic meta-analysis was undertaken to evaluate the value of combination therapy involving BEV in newly diagnosed GB. Methods: Electronic databases were searched for eligible literature up to October 2017. Randomized controlled trials assessing the efficacy and safety of BEV in patients with newly diagnosed GB were included, of which the main outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All the data were pooled with the corresponding 95% confidence intervals (CIs) using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of six randomized controlled trials were included in this analysis. The experimental BEV group had significantly improved the overall PFS (OR =0.46, 95% CI =0.26–0.81, P=0.007), as well as PFS at 6 months (OR =3.47, 95% CI =2.85–4.22, P<0.00001) and PFS at 12 months (OR =2.02, 95% CI =1.66–2.46, P<0.00001), respectively. However, there were no significant differences in PFS at 24 months with BEV (OR =0.95, 95% CI =0.61–1.48, P=0.82). OS at 6 months (P=0.07) and 24 months (P=0.07) was not significantly improved with BEV in patients with newly diagnosed GB. However, the meta-analysis on the OS at 12 months showed differences with BEV (OR =1.24, 95% CI =1.03–1.50, P=0.02). Conclusion: Our study indicates that addition of BEV for newly diagnosed GB resulted in a superior PFS rate. However, the combination therapy involving BEV did not improve OS. Future investigations are needed to analyze whether BEV helps improve OS efficacy. Keywords: bevacizumab, glioblastoma, newly diagnosed, meta-analysis, neoadjuvant

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The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis

OncoTargets and Therapy The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis Ke-li liao 1 song huang 1 Yu-Peng Wu 0 0 Department of n eurosurgery, The second hospital of hebei Medical University , shijiazhuang, hebei, People's republic of china 1 Department of n eurosurgery, Zigong First People's hospital , Zigong, sichuan, People's republic of china 8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon PowerdbyTCPDF(ww.tcpdf.org) Background: A combination of temozolomide (TMZ) and radiotherapy and subsequent adjuvant chemotherapy is the gold standard of treatment for glioblastoma (GB). Bevacizumab (BEV), a humanized monoclonal antibody that blocks the effects of vascular endothelial growth factor A, has produced impressive response rates for recurrent GB and has been approved as second-line therapy. The efficacy and safety of BEV in newly diagnosed GB are not known. Aim: This systematic meta-analysis was undertaken to evaluate the value of combination therapy involving BEV in newly diagnosed GB. Methods: Electronic databases were searched for eligible literature up to October 2017. Randomized controlled trials assessing the efficacy and safety of BEV in patients with newly diagnosed GB were included, of which the main outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All the data were pooled with the corresponding 95% confidence intervals (CIs) using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of six randomized controlled trials were included in this analysis. The experimental BEV group had significantly improved the overall PFS (OR =0.46, 95% CI =0.26-0.81, P=0.007), as well as PFS at 6 months (OR =3.47, 95% CI =2.85-4.22, P,0.00001) and PFS at 12 months (OR =2.02, 95% CI =1.66-2.46, P,0.00001), respectively. However, there were no significant differences in PFS at 24 months with BEV (OR =0.95, 95% CI =0.61-1.48, P=0.82). OS at 6 months (P=0.07) and 24 months (P=0.07) was not significantly improved with BEV in patients with newly diagnosed GB. However, the meta-analysis on the OS at 12 months showed differences with BEV (OR =1.24, 95% CI =1.03-1.50, P=0.02). Conclusion: Our study indicates that addition of BEV for newly diagnosed GB resulted in a superior PFS rate. However, the combination therapy involving BEV did not improve OS. Future investigations are needed to analyze whether BEV helps improve OS efficacy. - (anti-VEGF) agent, bevacizumab (BEV) serves as a potentially therapeutic option for GB.6 Based on the promising outcomes of two Phase II trials, the US Food and Drug Administration (FDA) has approved BEV in the second-line treatment of recurrent GB in 2009.14 The addition of BEV produces impressive progression-free survival (PFS) and response rate compared to standard treatment for recurrent GB, while the value of BEV on OS is still a matter of debate.7–9 At the time of the approval of BEV in recurrent disease, several randomized controlled trials (RCTs) were launched to investigate the value of BEV in addition to the treatment for newly diagnosed GB.10–15 Treatment combined with BEV exhibited significant activity in PFS for newly diagnosed GB patients, while further evaluation is needed to assess disease progression after antiangiogenic therapy. In order to make care for newly diagnosed GB more rational, we conducted a meta-analysis of RCTs to evaluate the therapeutic value of BEV compared with standard therapy (ST). eligibility criteria Studies that met the following criteria were included in the meta-analysis: 1) the studies were designed as RCTs; 2) studies focused on newly diagnosed GB treated with BEV; 3) the outcomes of interest regarding the treatment efficacy (survival), safety (adverse events [AEs]), and hazard ratios (HRs) with corresponding 95% CIs were provided; 4) only the full texts were included. The studies that did not meet the above inclusion criteria were excluded from the meta-analysis. Quality assessment Study quality was assessed using the Jadad seven-item scale recommended by The Cochrane Handbook for Systematic Reviews of Interventions. The Jadad seven-item scale was introduced to evaluate the overall methodological quality of RCTs. 3514 Data extraction The data extraction was conducted independently by two authors. Disagreement was revolved by consensus. The main characteristics extracted from the selected studies were the following: first author family name, publication year, trial name, study design, sample size, and the outcomes of interest (AEs, PFS, and OS). The corresponding hazard ratios (HRs) with 95% confidence intervals (CIs) were used to describe the main outcomes of the studies, including OS, PFS, and AE data, and 95% CIs were calculated for each estimate. statistical analysis The main outcomes of the studies were OS, PFS, and AEs. If HRs and corresponding 95% CIs were reported, the lnHRs and the corresponding ln lower limits and ln upper limits were used as data points in pooling analysis. While, if the study did not provide HRs or 95% CIs, the only available data were in the form of Kaplan–Meier (K–M) curves. Survival data were extracted from the form of the K–M survival curve, according to the methods described by Tierney et al.16 The I 2 statistical test was used to further examine statistical heterogeneity between the trials.17 Studies with an I 2$50% were considered to exhibit moderate and high heterogeneity, and those with I 2,50% were considered to have low heterogeneity.18 Summary HRs were calculated by using fixed-effect models when there was low heterogeneity among studies. Otherwise, random-effect models were used. A P-value ,0.05 was considered to be statistically significant. All analyses were conducted with Review Manager Version 5.3 software (Revman; The Cochrane Collaboration, Oxford, UK). Findings of our meta-analysis are shown in forest plots. The Begg’s test and the Egger’s test were used to evaluate publication bias. Results search results and characteristics of studies A total of 214 studies were retrieved initially for evaluation. Based on the criteria described in the “Methods” section, 10 publications were evaluated in more detail, but some did not provide enough detail of the outcomes of two approaches. Therefore, we had a final total of six RCTs10–15 assessing the value of BEV in patients with newly diagnosed GB. The search process is described in Figure 1. All included papers in this study were based on moderateto high-quality evidence. Table 1 describes the primary characteristics of the eligible studies in more detail. clinical and methodological heterogeneity Pooled analysis of PFs comparing the addition of BeV with the control group Pooling the PFS data from five studies10,11,13–15 showed that BEV prolonged the PFS (HR =0.69, 95% CI =0.63–0.77, P,0.00001) compared with the control group (Figure 2). subgroup analysis of PFs comparing the addition of BeV with the control group Overall, the six studies that reported data on PFS at different months are shown in Figures 3–5. Pooled data showed that the PFS data achieved advantage with BEV agents, with the pooled OR being 3.47 (95% CI 2.85–4.22, P,0.00001) at 6 months (Figure 3); 2.02 (95% CI 1.66–2.46, P,0.00001) at Experiment Control Experiment Control Experiment 8 1 0 2 l u J 3 1 n o 027 12 months (Figure 4); and 0.95 (95% CI 0.61–1.48, P=0.82) ..46 at 24 months (Figure 5). In other words, the addition of .759 BEV agents increases the PFS. 3 /yb Pooled analysis of Os comparing the addition of BeV .com with the control group rsse . A random-effects model was used to pool the OS data.10,11,13–15 .vdoep lsyeon The pooled data showed that a BEV agent plus chemotherapy w u did not improve the OS (HR =0.91, 95% CI =0.76–1.08, //:ww lano P=0.28) than the control treatment (Figure 6). tsp rse th rp subgroup analysis of Os comparing the addition of from oF BeV with the control group edd Subgroup analysis of OS data at different months was availloan able for all six RCTs.10–15 Analysis showed that the results odw of OS at 6 months (HR =1.28, 95% CI =0.98–1.67, P=0.07) yap (Figure 7) with BEV were no longer significant in patients reh with newly diagnosed GB, while the meta-analysis on the dnT OS at 12 months showed differences with BEV (HR =1.24, tsae 95% CI =1.03–1.50, P=0.02) (Figure 8). However, OS at rga 24 months still did not reach statistically significant difference cnoT (HR =1.22, 95% CI =0.98-1.52, P=0.07) (Figure 9). O Pooled analysis of aes comparing the addition of BeV with the control group Due to the limited data in all studies, systematic evaluations of AE data were not possible in this meta-analysis. Gilbert et al13 report that toxicities, hypertension, thromboembolic events, intestinal perforation, and neutropenia were observed in the BEV group. Over time, patients treated with BEV have an increased symptom burden following a worse QoL, as well as debilitating neurological symptoms. In Chinot et al,14 grade 3 or higher AEs (66.8% vs 51.3%) were more frequent in the BEV group. Discussion GB is the most frequent malignant brain tumor with a poor prognosis. Patients with recurrent GBs have a poor OS, and available therapies have a limited impact on prognosis. Therefore, development of a new approach is essential to improve the outcomes in patients with newly diagnosed GB. In Phase III RCTs,3 the addition of TMZ to chemoradiotherapy (CRT) and subsequent adjuvant chemotherapy has been the standard therapy with newly diagnosed GB and is thought to be the backbone for further understanding therapy choices.19 Research reports have shown that GB has multistep cytostatic effects that alter neovascularization of brain tissue to form new blood vessels, which may help slow tumor progression and proliferation.20,21 VEGF is overexpressed in malignant gliomas and has been used as a therapeutic target for brain tumors.22 BEV, a humanized monoclonal antibody against the VEGF ligand, has received FDA approval for recurrent χ χ 3516 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon w u /ww lan /: o tsp rse th rp Study or subgroup Chauffert et al, 201411 Balana et al, 201610 Carlson et al, 201512 Gilbert et al, 2014 13 Chinot et al, 2014 14 Herrlinger et al, 201615 GBMs in 2009.23–25 The results have suggested that a potential benefit could be achieved by BEV for newly diagnosed GB.26 To assess whether BEV would be safe and effective for the treatment of newly diagnosed GB, we conducted a meta-analysis to evaluate the value of therapy with the combination of BEV. All included studies chose OS and PFS as the primary end points. At the time of disease progression, crossover regimen may continue to benefit patients following an initial response to therapy with or without BEV. Therefore, in newly diagnosed GBs, the end point of PFS has beneficial effects in evaluating the potential effects of combined treatment with BEV than OS.13 Data from the trial of Carlson et al,12 showed that compared with placebo plus TMZ and radiotherapy, the combination using BEV did not improve OS, but increases PFS, although it is statistically nonsignificant (P=0.39). In the AVAglio and RTOG 0825 studies,13,14 the PFS was significantly improved with the addition of BEV, but OS did not show benefit. In this study, we conclude that the combination of BEV for newly diagnosed GB is beneficial in terms of prolonging median PFS but not OS. Our results did not indicate any benefit from BEV for newly diagnosed GB in terms of median OS. The AVAglio, RTOG 082512, and GLARIUS13–15 trials obtained similar results. In our analysis, the pooled analysis did not show that the PFS benefit translates into OS prolongation. As potential reasons for this observation, patients with GB exhibited worse neurocognition and poor survival rate with prolonged use of BEV, which might be caused by BEV resistance. Resistance to chemotherapy was considered to influence the effectiveness of BEV treatment for GB. As an antiangiogenic (anti-VEGF) agent, BEV has been investigated as complementary to standard chemotherapy to suppress tumor growth.27 Due to the different angiogenesis pathways of the VEGF genes, there may be benefit in continuing BEV treatment even after resistance to chemotherapy.28–30 However, the potential antitumor effects underlying resistance to antiangiogenic agents are yet to be fully evaluated. The point of molecular signatures may reveal subsets of GBs that are particularly sensitive or resistant to BEV. In additional analyses of subgroups of patients based on different genetic mutations, we may identify patients who had a selected survival benefit response to BEV. Furthermore, BEV’s radiographic effect has been reported to be associated with an increased incidence of PFS. BEV stabilizes the blood–brain barrier, minimizing the ability of the magnetic resonance imaging (MRI) contrast agent gadolinium to reach the tumor, thus χ submit your manuscript | www.dovepress.com Dovepress 3517 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon showing “improved” or “cleaner” MRIs, hence delaying the BEV therapy does not have a place in ST with newly diagdiagnosis of progression (a largely radiographic diagnosis) nosed GB. We suggest that studies of correlative molecular and consequently showing prolonged PFS. Moreover, secondsignatures are needed to identify particular subgroups of line crossover BEV therapy has been shown to play an imporpatients who will receive benefit from the combination of tant role in the OS. Therefore, there is much more detailed BEV. Further research is needed to define the best treatment knowledge on postprogression therapy. In GLARIUS,15 response with the lowest possible toxicity in selecting suitpatients who received the crossover BEV therapies achieved able patients with consideration for their complications and a significant OS benefit compared with other BEV first-line treatment regimen. trials. The RPSFT analysis, which evaluated the influence of crossover BEV treatment, suggested a significant OS benefit Disclosure of the combination therapy of BEV and thus indicates that The authors report no conflicts of interest in this work. BEV crossover may be associated with OS prolongation.15 To date, the mechanism of long-term BEV treatment has not been established. Further studies of other physiological molecularly defined subgroups may suggest a potential marker panel for BEV, which would need more clinical trials to clarify. In previous studies, the serious AEs observed more frequently in the BEV group included abdominal pain, headache, fatigue, hypertension, diarrhea, neutropenia, complications of wound healing, cerebral hemorrhage or ischemia, gastrointestinal perforation, congestive heart failure, and anemia.13,14 Due to the limited data shown in all studies, systematic evaluations of AE data were not possible in this meta-analysis. In a previous meta-analysis, BEV therapy was not found to be associated with serious AEs for newly diagnosed GB.31 However, the authors did indicate a trend toward significance with respect to BEV treatment.31 In this systematic analysis assessing the value of BEV in the treatment of newly diagnosed GB, there are some limitations that should not be ignored. First, as only full texts were included and this study was a study-level meta-analysis, which resulted in imbalance between the two groups, clinical heterogeneity among trials should be taken into consideration in the interpretation of our findings. Second, most included studies reported short-term survival rates within 2 years of follow-up. There were insufficient data to determine long-term survival rate. Further studies are needed to report survival rates at 3 years or longer follow-ups. Third, as the data on AEs in the included trials is limited, we did not perform the analysis of AEs in this meta-analysis. Conclusion BEV treatment has a potential benefit in terms of PFS, but not OS. The apparent lack of OS benefit is probably associated with the confounding effects of crossover, although many other explanations are possible. On the basis of all available studies (AVAglio, RTOG 0825, and GLARIUS),13–15 submit your manuscript | www.dovepress.com Dovepress 3519 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon Publish your work in this journal OncoTargets and Therapy is an international, peer-reviewed, open access journal focusing on the pathological basis of all cancers, potential targets for therapy and treatment protocols employed to improve the management of cancer patients. The journal also focuses on the impact of management programs and new therapeutic agents and protocols on 1. Stupp R , Pavlidis N , Jelic S , Force EGT . ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of malignant glioma . 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Ke-Li Liao, Song Huang, Yu-Peng Wu. The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis, OncoTargets and Therapy, 2018, 3513-3520, DOI: 10.2147/OTT.S156723